Faculty Bibliography

BACKGROUND:TIL enumeration. METHODS:TIL enumeration in prognosticating TNBC using immunohistochemistry on whole tissue sections and quantification by digital image analysis (Halo imaging analysis software; Indica Labs, Corrales, NM). A wide range of clinically relevant hot spot sizes was evaluated. RESULTS:TIL enumeration did not (P > .05). Statistical significance was not demonstrated when comparing between hot spots and whole-tumor annotations, as the groups had overlapping confidence intervals. CONCLUSION:TIL hot spot enumeration is equivalent to whole-tumor enumeration for prognostication in TNBC and may serve as a good alternative methodology in future studies and clinical practice.

Mammary myofibroblastoma is a benign spindle cell tumor that can show variable morphologic patterns and lines of differentiation. Diffuse and strong immunohistochemical expression of CD34 is a characteristic of myofibroblastoma and greatly aids in confirming a diagnosis. Myofibroblastoma has been shown to belong to a family of CD34-positive tumors with similar morphology that show a deletion of 13q14, which includes RB1 and FOXO1A genes. The purpose of this study was to better understand a subset of myofibroblastomas that is characteristically CD34-deficient by immunohistochemistry. Six myofibroblastomas were studied by immunohistochemistry and fluorescence in situ hybridization (FISH) for RB1. Patients included five women and one man, aged 41-85 years (median, 52.5). Tumor size ranged from 0.4 to 1.5 cm (mean, 0.95). Tumors showed spindle cell morphology in five cases and epithelioid features in one case. Two tumors showed complete lack of CD34 staining. The remaining showed weak focal or weak patchy CD34 staining. Dichotomous staining was seen in one case with CD34-positive spindle cell areas and CD34-negative myxoid areas. All six tumors showed ER expression, five of six showed desmin expression, and four of six showed bcl-2 positivity. Two of six (33.3%) tumors showed deletion of RB1 by FISH, including one that showed loss of Rb immunohistochemical staining. Myofibroblastomas uncommonly show absent/focal expression of CD34, a potential diagnostic pitfall, particularly in small samples. Characteristic staining with other immunohistochemical markers is seen which can aid in confirming the diagnosis. These tumors may harbor deletion of RB1, similar to CD34-positive myofibroblastomas, and this deletion may not correlate with loss of Rb by immunohistochemistry.

CONTEXT/BACKGROUND:- Lobular carcinoma in situ (LCIS) refers to a neoplastic proliferation of cells that characteristically shows loss of E-cadherin expression and has long been regarded as a risk factor for invasive breast cancer. Long-term outcome studies and molecular data have also implicated LCIS as a nonobligate precursor to invasive carcinoma. In the past few decades, pleomorphic and florid LCIS have been recognized as morphologic variants of LCIS with more-aggressive histopathologic features, less-favorable biomarker profiles, and more-complex molecular features compared with classic LCIS. There is still a lack of consensus regarding certain aspects of managing patients with LCIS. OBJECTIVES/OBJECTIVE:- To review recently published literature on LCIS and to provide an overview of the current morphologic classification of LCIS, recent molecular advances, and trends in patient management. DATA SOURCES/METHODS:- Sources included peer-reviewed, published journal articles in PubMed (US National Library of Medicine, Bethesda, Maryland) and published guidelines from the National Comprehensive Cancer Network (Fort Washington, Pennsylvania). CONCLUSIONS:- Lobular carcinoma in situ represents a marker for increased risk of breast cancer, as well as a nonobligate precursor to invasive carcinoma. Morphologic variants of LCIS-florid and pleomorphic LCIS-are genetically more-complex lesions and are more likely to be associated with invasive carcinoma. Further investigation into which molecular alterations in LCIS are associated with progression to invasive carcinoma is needed to help guide medical and surgical management.

BACKGROUND:Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in breast cancer. The limited studies evaluating the role of FOLR1 in breast cancer have shown that FOLR1 protein expression is enriched in triple-negative breast cancer (TNBC) and associated with poor prognosis in all breast cancer types. Newly developed anti-FOLR1 therapy could potentially be used in patients with TNBC for whom few therapeutic options exist. We sought to evaluate FOLR1 protein expression in a cohort of patients with TNBC to determine its prevalence and prognostic value. MATERIALS:Immunohistochemistry was performed for FOLR1 in 76 cases of primary TNBC. Membranous staining in ≥ 5% of cells was deemed positive in a given case. Statistical analyses correlating FOLR1 protein expression with clinicopathologic parameters and clinical outcome (disease-free survival and overall survival) were performed. RESULTS:A total of 76 cases of primary TNBC were studied. Most cases were negative for FOLR1 (80.3%; 61/76). FOLR1 expression did not correlate with any clinicopathologic parameters. FOLR1 expression was significantly correlated with decreased disease-free survival (hazard ratio, 2.61; 95% confidence interval, 0.96-7.09; P = .0497 log-rank test). Although FOLR1 expression trended towards decreased overall survival, it was not statistically significant (hazard ratio, 1.99; 95% confidence interval, 0.62-6.36; P > .05 log-rank test). CONCLUSION:We found a lower incidence of FOLR1 expression in TNBC compared with other studies; however, these patients may benefit from anti-folate therapy as other targeted therapies are not available. Although no correlation between FOLR1 expression and standard clinicopathologic parameters was identified, our findings suggest that FOLR1 expression is prognostically significant in TNBC.

Intraoperative radiotherapy (IORT) is a novel and increasingly utilized radiation technique in the treatment of breast carcinoma. There are few reports on the histologic changes seen in breast tissue from patients who have undergone IORT. We sought to evaluate the histologic changes observed in specimens received following IORT, as well as report an unusual case which prompted our study. A retrospective review of patients who received IORT and subsequently had breast tissue histologically evaluated at our institution was performed. Fifteen post-IORT specimens from 12 patients, including the patient from the reported case, were studied. We report a case of a 77-year-old woman found to have mammographic microcalcifications at the lumpectomy site 6 months following lumpectomy and IORT for ductal carcinoma in situ (DCIS). A stereotactic biopsy showed abundant desquamated anucleate squamous cells with calcification and keratin material associated with squamous metaplasia of ducts. Carcinoma was not present. The predominant findings in the post-IORT specimens were fat necrosis and scar (n = 5), recurrent invasive carcinoma (n = 5), surgical site changes (n = 3), abscess (n = 1), and exuberant squamous metaplasia with calcification (n = 1). Five of fifteen (33%) post-IORT specimens showed squamous metaplasia, all of which were collected within 6 months of IORT delivery. The morphologic changes observed after IORT are similar to those seen after external beam radiotherapy. Exuberant squamous metaplasia is an uncommon consequence of IORT; however, pathologists should be aware of this phenomenon and review a history of prior intraoperative radiation before raising concern for malignancy.

Subareolar sclerosing duct hyperplasia (SSDH) remains to be fully characterized nearly 20 years after initial description. Thirty-five SSDH cases diagnosed over a 16-year period (January 2000 to December 2015) were reviewed. All patients were female (mean age = 59 years, range = 18-80) who had presented with a unilateral solitary lesion (left 22, right 13) with a mean size of 1.3 cm (range = 0.4-3.0 cm), and showed florid and papillary epithelial hyperplasia with dense sclerosis without involvement of nipple or areolar epidermis. Significant lesions concurrent within SSDH included low-grade adenosquamous carcinoma (n = 1), ductal carcinoma in situ (DCIS; n = 1), lobular carcinoma in situ (LCIS; n = 1), and atypical ductal hyperplasia (ADH; n = 13). No case of SSDH recurred in a mean follow-up of 44 months (range = 6-189). Subsequent significant lesions occurred in 6 patients: DCIS (n = 3; ipsilateral 2, contralateral 1), ipsilateral ADH (n = 2), and ipsilateral atypical lobular hyperplasia (n = 1). Long-term follow-up for patients with SSDH is indicated as DCIS can occur subsequently in either breast.

Vascular proliferations of the breast comprise a spectrum of benign and malignant lesions. In limited samples, such as core needle biopsies (CNB), these lesions may be difficult to distinguish due to significant overlap in morphological features. As the treatment and prognosis of these entities vary widely, it is important for pathologists to consider a complete differential diagnosis and correctly synthesise histological features, results of adjunctive immunohistochemical studies, and pertinent clinical and imaging information, to render an accurate diagnosis in such limited samples. The diagnostic pitfalls of under- or overdiagnosis of vascular lesions sampled in CNB will also be discussed.

Mammary myofibroblastoma is a benign spindle cell tumor that can show variable morphologic patterns and lines of differentiation. Myofibroblastoma belongs to a family of CD34-positive tumors with similar morphology that show a deletion of 13q14, which includes RB1 and FOXO1A genes. A subset of these tumors demonstrates distinct smooth muscle differentiation. We aimed to characterize 4 cases of the leiomyomatous variant of myofibroblastoma arising in the breast by clinicopathological, immunohistochemical, and molecular means. All 4 examples arose in women aged 41 to 62 years (median, 46.5 years). Tumors ranged in size from 1.7 to 2.5 cm (median, 2.2 cm). Morphologically, all tumors were characterized by bundles of smooth muscle cells with elongated cigar-shaped nuclei and eosinophilic cytoplasm. All 4 tumors showed diffuse positive staining with desmin, caldesmon, smooth muscle actin, estrogen receptor, and Bcl-2. CD34 staining was diffusely positive in 2 cases, was weak and patchy in 1 case, and was negative in 1 case. Two (50%) of 4 tumors showed deletion of RB1 by fluorescence in situ hybridization. Loss of Rb staining was seen in 1 tumor with RB1 deletion by fluorescence in situ hybridization, whereas intact Rb staining was observed in 1 nondeleted case studied. In conclusion, this rare variant of myofibroblastoma is a distinct subgroup of tumors among an already uncommon category of (smooth muscle) breast tumors. Some reported examples of "parenchymal leiomyoma" may represent the leiomyomatous variant of myofibroblastoma.